Substituted 2-benzylamino-2-phenyl-acetamide compounds

ABSTRACT

Compounds which are substituted 2-benzylamino-2-phenyl-acetamide compounds of formula (I)wherein:n is zero, 1, 2 or 3;X is -O-, -S-, -CH2- or -NH-;each of R, R1, R2 and R3, independently, is hydrogen, C1-C6 alkyl, halogen, hydroxy, C1-C6 alkoxy or trifluoromethyl;each of R4 and R5, independently, is hydrogen, C1-C6 alkyl or C3-C7 cycloalkyl; or pharmaceutically acceptable salts thereof, are useful in treating conditions such as chronic or neuropathic pain.

This application is a 371 of PCT/EP98/08159 filed Dec. 12, 1998.

The present invention relates to novel substituted2-benzylamino-2-phenyl-acetamide compounds, to a process for theirpreparation, to pharmaceutical composition containing them and to theiruse as therapeutic agents.

In particular, the compounds provided by the present invention aresodium channel blockers, and thus exhibit useful pharmacologicalproperties, especially for the treatment and alleviation of chronic andneuropathic pain. Chronic and neuropathic pain are associated withprolonged tissue damage or injuries to the peripheral or central nervoussystem and result from a number of complex changes in nociceptivepathways, including ion channel function. Clinical manifestations ofchronic pain include a sensation of burning or electric shock, feelingsof bodily distortion, allodynia and hyperpathia.

Despite the large number of available analgesics, their use is limitedby severe side effects and modest activity in some pain conditions.Therefore there is still a clear need to develop new compounds.

Accordingly, one object of the present invention is to provide novelcompound having the following formula (I)

wherein:

n is zero, 1, 2 or 3;

X is —O—, —S—, —CH₂— or —NH—; each of R, R₁, R₂ and R₃, independently,is hydrogen, C₁-C₆ alkyl, halogen, hydroxy, C₁-C₆ alkoxy ortrifluoromethyl;

each of R₄ and R₅, independently, is hydrogen, C₁-C₆ alkyl or C₃-C₇cycloalkyl; and the pharmaceutically acceptable salts thereof.

A —(CH₂)_(n)— chain may be a branched or straight chain.

Alkyl and alkoxy groups may be branched or straight groups.Representative examples of C₁-C₆ alkyl groups include C₁-C₄ alkyl groupssuch as methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert-butyl.

Representative examples of C₁-C₆ alkoxy groups include C₁-C₄ alkoxygroups such as methoxy and ethoxy.

A C₃-C₇ cycloalkyl group is for instance cyclopropyl, cyclopentyl orcyclohexyl, in particular cyclopentyl or cyclohexyl.

A halogen atom is fluorine, bromine, chlorine or iodine, in particular,chlorine or fluorine.

Pharmaceutically acceptable salts of the compounds of the inventioninclude acid addition salts with inorganic, e.g. nitric, hydrochloric,hydrobromic, sulphuric, perchloric and phosphoric acids or organic, e.g.acetic, trifluoroacetic, propionic, glycolic, lactic, oxalic, malonic,malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic andsalicylic acids.

The compounds of the invention have asymmetric carbon atoms andtherefore they can exist either as racemic mixtures or as individualoptical isomers (enantiomers).

Accordingly, the present invention also include within its scope all thepossible isomers and their mixtures and both the metabolites and thepharmaceutically acceptable bio-precursors (otherwise known aspro-drugs) of the compounds of the invention.

Preferred compounds of the invention are the compounds of formula (I)wherein

n is 1 or 2;

X is —O—;

each of R, R₁, R₂ and R₃, independently, is hydrogen, or halogen;

R₄ and R₅ are hydrogen; and the pharmaceutically acceptable saltsthereof.

Examples of specific compounds of the invention are:

2-[4-benzyloxybenzylamino]-2-phenyl-acetamide;

2-[4-(3-fluorobenzyloxy)benzylamino]-2-phenyl-acetamide;

2-[4-(3-chlorobenzyloxy)benzylamino]-2-phenyl-acetamide;

2-[4-(3-bromobenzyloxy)benzylamino]-2-phenyl-acetamide;

2-[4-(2-fluorobenzyloxy)benzylamino]-2-phenyl-acetamide;

2-[4-(3-fluorobenzyloxy)benzylamino]-2-(2-fluorophenyl)-acetamide;

2-[4-(3-fluorobenzyloxy)benzylamino]-2-(3-fluorophenyl)-acetamide; and

2-[4-(3-chlorobenzyloxy)benzylamino]-2-(3-fluorophenyl)-acetamide,

if the case either as a single isomer or as a mixture thereof, and thepharmaceutically acceptable salts thereof.

Object of the present invention is also to provide a compound of formula(I), as defined above, or a pharmaceutically acceptable salt thereof foruse as a therapeutic substance, in particular for treating chronic andneuropathic pain.

An aspect of this invention relates to the use of a compound of formula(I), as defined above, or a pharmaceutically acceptable salt thereof inthe manufacture of a medicament for use in treating chronic andneuropathic pain.

A further aspect of this invention relates to a method of treating amammal, including humans, in need of a sodium channel-blocking agent,said method comprising administering thereto an effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.

Neuropathic pain conditions in a mammal can thus be alleviated andtreated. Examples of neuropathic pain conditions responsive to sodiumchannel-blocking agents include:

peripheral neuropathies, such as trigeminal neuralgia, postherapeuticneuralgia, diabetic neuropathy, glossopharyngeal neuralgia,radiculopathy, and neuropathy secondary to metastatic infiltration,adiposis dolorosa and burn pain; and

central pain conditions following stroke, thalamic lesions and multiplesclerosis.

‘Treatment’ as used herein covers any treatment of a condition in amammal, particularly a human, and includes:

(i) preventing the disease from occurring in a subject which may bepredisposed to the disease, but has not yet been diagnosed as having it;

(ii) inhibiting the condition, i.e., arresting its development; or

(iii) relieving the condition, i.e., causing regression of the disease.

The term ‘disease state which is alleviated by treatment with a sodiumchannel blocker’ as used herein is intended to cover all disease stateswhich are generally acknowledged in the art to be usefully treated withsodium channel blockers in general, and those disease states which havebeen found to be usefully treated by the specific sodium channel blockerof our invention, the compound of formula (I).

The compounds of the invention and the salts thereof can be obtained,for instance, by a process comprising:

a) reacting a compound of formula (II)

wherein n, R₂, R₃ and X are as defined above, with a compound of formula(III)

wherein R, R₁ and R₄ are as defined above, thus obtaining a compound offormula (I) in which R₅ is hydrogen; or

b) reacting a compound of formula (IV)

wherein R, R₁, R₂, R₃, R₄, n and X are as defined above, with a compoundof formula (V), (VI) or (VII)

R′₅W  (V)

R″₅CHO  (VI)

wherein W is a halogen atom; R′₅ is a C₁-C₆ alkyl or C₃-C₇ cycloalkyland R″₅ is hydrogen or C₁-C₅ alkyl, and p is 2-6, thus obtaining acompound of the invention in which R₅ is C₁-C₆ alkyl or C₃-C₇cycloalkyl; and, if desired, converting a compound of the invention intoanother compound of the invention and/or, if desired, converting acompound of the invention into a pharmaceutically acceptable saltand/or, if desired, converting a salt into a free compound.

All the processes described hereabove are analogy processes and can becarried out according to well known methods in organic chemistry.

A compound of formula (IV) is a compound of formula (I) in which R₅ ishydrogen.

The reaction of a compound of formula (II) with a compound of formula(III) to give a compound of formula (I) or (IV) is a reductive aminationreaction which can be carried out according to well known methods.According to a preferred embodiment of the invention it may be performedunder nitrogen atmosphere, in a suitable organic solvent, such as analcohol, e.g. a lower alkanol, in particular methanol, or inacetonitrile, at a temperature ranging from about 0° C. to about 40° C.,in the presence of a reducing agent, the most appropriate being sodiumcyanoborohydride.

Occasionally molecular sieves can be added to the reaction mixture forfacilitating the reaction.

In a compound of formula (V) the halogen W is preferably iodine. Thealkylation reaction of a compound of formula (IV) with a compound offormula (V) can be carried out in a suitable organic solvent, such as analcohol, e.g. methanol, ethanol or isopropanol, in particular inethanol, at a temperature ranging from about 0° C. to about 50° C.

The alkylation reaction of a compound of formula (IV) with an aldehydeof formula (VI) or (VII) can be carried out in a suitable organicsolvent, such as an alcohol, e.g. methanol, ethanol or acetonitrile inthe presence of a suitable reducing agent, such as sodiumcyanoborohydride, at a temperature ranging from about 0° C. to about 30°C.

A compound of the invention can be converted, as stated above, intoanother compound of the invention by known methods. Process-variant b)above may be regarded as an example of optional conversion of a compoundof the invention into another compound of the invention.

Also the optional salification of a compound of the invention as well asthe conversion of a salt into the free compound may be carried out byconventional methods.

The compounds of formula (II) and (III), (V), (VI) and (VII) are knowncompounds or can be obtained by known methods.

When in the compounds of the present invention and in theintermediate-products thereof, groups are present, which need to beprotected before submitting them to the hereabove illustrated reactions,they may be protected before being reacted and then deprotectedaccording to methods well known in organic chemistry.

Pharmacology

As stated above, the compounds of the invention are sodiumchannel-blocking agents, as proven for instance by the fact that theybind to site-2 (labeled by ³H-Batrachotoxin) on the rat brain sodiumchannel.

Interaction of the compounds with the site 2 of the sodium channel wasevaluated in rat brain membranes using the ³H-batrachotoxin as ligand,according to published methods (Catterall, W. A., J. Biol. Chem., 1981,256, 8922-8927).

For instance, for the representative compound of the(R)-2-[4-(3-fluorobenzyloxy)benzylamino]-2-phenyl-acetamide,methanesulfonate (internal code PNU 190296 E) the following test datawere obtained.

TABLE 1 Na+ channel block Compound ³H-Batrachotoxin binding (μM) PNU190296E 0.39

In view of their biological activity, the compounds of the invention areuseful in therapy in the regulation of physiological phenomena relatedto sodium channel blockade, including arrhythmia, convulsion, painassociated with damage or permanent alteration of the peripheral orcentral nervous system, for example peripheral neuropathies, such astrigeminal neuralgia, postherapeutic neuralgia, diabetic neuropathy,raticulopathy, glossopharyngeal neuralgia, and neuropathy secondary tometastatic infiltration, adiposis dolorosa, and burn pain; and centralpain conditions following stroke, thalamic lesions and multiplesclerosis.

The conditions of a patient in need of a sodium channel-blocking agentmay thus be improved.

The compounds of the invention can be administered in a variety ofdosage forms, e.g. orally, in the form of tablets, capsules, sugar orfilm coated tablets, liquid solutions or suspensions; rectally in theform of suppositories; parenterally, e.g. intramuscularly, or byintravenous injection or infusion.

The dosage depends on the age, weight, conditions of the patient and onthe administration route; for example, the dosage adopted for oraladministration to adult humans e.g. for the representative compound ofthe invention(R)-2-[4-(3-fluorobenzyloxy)benzylamino]-2-phenyl-acetamide may rangefrom about 1 to about 500 mg pro dose, from 1 to 5 times daily.

The invention includes pharmaceutical compositions comprising a compoundof the invention, as an active principle, in association with apharmaceutically acceptable excipient (which can be a carrier or adiluent).

The pharmaceutical compositions containing the compounds of theinvention are usually prepared following conventional methods and areadministered in a pharmaceutically suitable form.

For example, the solid oral forms may contain, together with the activecompound, diluents, e.g. lactose, destrose, saccharose, cellulose, cornstarch or potato starch; lubricants, e.g. silica, talc, stearic acid,magnesium or calcium stearate, and/or polyethylene glycols; bindingagents, e.g. starches, arabic gums, gelatin, methylcellulose,carboxymethylcellulose or polyvinyl pyrrolidone; desegregating agents,e.g. a starch, alginic acid, alginates or sodium starch glycolate;effervescing mixtures; dyestuffs; sweeteners; wetting agents such aslecithin, polysorbates, laurylsulphates; and, in general, non-toxic andpharmacologically inactive substances used in pharmaceuticalformulations. Said pharmaceutical preparations may be manufactured inknown manner, for example, by means of mixing, granulating, tabletting,sugar-coating, or film-coating processes.

The liquid dispersion for oral administration may be e.g. syrups,emulsions and suspension.

The syrups may contain as carrier, for example, saccharose or saccharosewith glycerine and/or mannitol and/or sorbitol.

The suspension and the emulsion may contain as carrier, for example, anatural gum, agar, sodium alginate, pectin, methylcellulose,carboxymethylcellulose, or polyvinyl alcohol.

The suspension or solutions for intramuscular injections may contain,together with the active compound, a pharmaceutically acceptablecarrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g.propylene glycol, and, if desired, a suitable amount of lidocainehydrochloride. The solutions for intravenous injections or infusion maycontain as carrier, for example, sterile water or preferably they may bein the form of sterile, aqueous, isotonic saline solutions.

The suppositories may contain together with the active compound apharmaceutically acceptable carrier, e.g. cocoa butter, polyethyleneglycol, a polyoxyethylene sorbitan fatty acid ester surfactant orlecithin.

The following examples illustrate but do not limit the invention.

EXAMPLE 1 1. D-phenyglycinamide

30 g (0.149 mol) of D-phenylglycine methyl ester, hydrochloride weredissolved in dioxane (90 mL), then 90 mL of 30% NH₄OH solution wereadded dropwise. The mixture was stirred overnight, evaporated and thecrude residue flash-chromatographed on silica gel usingdichloromethane/methanol/30% NH₄OH; 165/35/3. The white solid obtainedwas dissolved in abs. EtOH and acidified with an excess of 10% HCl inETOH. The solution was evaporated, taken up with diethyl ether (Et₂O),the white solid precipitated was filtered and washed with Et₂O, yielding12.2 g (69%) of pure compound.

[α]_(D) ²⁵+99.6 (c=1.1, MeOH)

2. (R)-2-[4-(3-fluorobenzyloxy)benzylamino]-2-phenyl-acetamide,methanesulfonate

A mixture of D-phenylglycinamide hydrochloride (4.45 g; 0.022 mol) and3A molecular sieves (4.45 g) in MeOH (150 mL) was stirred under nitrogenfor 10 minutes, then treated with sodium cyanoborohydride (1.09 g; 0.016mol) and 4-(3-fluorobenzyloxy)benzaldehyde (5 g; 0.022 mol). The mixturewas stirred at room temperature for 4 hours, then filtered, the residueevaporated and flash-chromatographed on silica gel usingdichloromethane/methanol/30% NH4OH; 95/5/0.5) as eluant. 5.3 g (53%) ofa crystalline white solid were obtained after treatment with an excessof methanesulfonic acid in ethyl acetate and filtration.

m.p. 227-231° C.;

[α]_(D) ²⁵−50.2 (c=1.1, AcOH);

Elemental Analysis:

Atom Calc. Found C 59.98 59.17 H 5.47 5.46 N 6.08 6.04 S 6.96 7.30

Analogously, starting from the appropriate aldehyde and aminoamide, thefollowing compounds can be prepared:

2-[4-benzyloxybenzylamino]-2-phenyl-acetamide methanesulfonate;

2-[4-(3-chlorobenzyloxy)benzylamino]-2-phenyl-acetamidemethanesulfonate;

2-[4-(3-bromobenzyloxy)benzylamino]-2-phenyl-acetamide methanesulfonate;

2-[4-(2-fluorobenzyloxy)benzylamino]-2-phenyl-acetamidemethanesulfonate;

2-[4-(3-fluorobenzyloxy)benzylamino]-2-(2-fluorophenyl)-acetamidemethanesulfonate;

2-[4-(3-fluorobenzyloxy)benzylamino]-2-(3-fluorophenyl)-acetamidemethanesulfonate;

2-[4-(3-chlorobenzyloxy)benzylamino]-2-(3-fluorophenyl)-acetamidemethanesulfonate;

2-[4-(3-fluorobenzylamino)benzylamino]-2-phenyl-acetamidemethanesulfonate; and

2-[4-(3-fluorobenzylthio)benzylamino]-2-phenyl-acetamidemethanesulfonate.

EXAMPLE 2(R)-2-[[4-(3-fluorophenyloxy)benzyl]-2-methyl-amino]-2-phenyl-acetamide

4 g (0.011 mol) of(R)-2-[4-(3-fluorophenyloxy)benzylamino]-2-phenyl-acetamide weredissolved in methanol (50 mL) and 1.8 g (0.013 mol) of anhydrouspotassium carbonate were added to the solution. Methyl iodide (1.5 mL;0.025 mol) was dropped into the mixture which was stirred for 2 hours atroom temperature and then evaporated to dryness. The crude residue waschromatographed on silica gel (eluant: chloroform/methanol; 95/5). 2.11g (51%) of(R)-2-[[4-(3-fluorophenyloxy)benzyl]-2-methyl-amino]-2-phenyl-acetamidewere obtained.

Elemental Analysis:

Atom Calc. Found C 73.00 73.35 H 6.13 6.18 F 5.02 5.00 N 7.40 7.29

Analogously, the following compounds can be obtained and, if required,salified with a suitable acidic agent according to known methods:

(R)-2-[[4-(3-chlorophenyloxy)benzyl]-2-methyl-amino]-2-phenyl-acetamide;

(S)-2-[[4-(3-fluorophenyloxy)benzyl]-2-methyl-amino]-2-phenyl-acetamide;

(R)-2-[[4-(3-bromophenyloxy)benzyl]-2-methyl-amino]-2-phenyl-acetamide;

(R)-2-[[4-(3-fluorophenyloxy)benzyl]-2-ethyl-amino]-2-phenyl-acetamide;

(R)-2-[(4-phenyloxybenzyl)-2-methyl-amino]-2-phenyl-acetamide;

(S)-2-[(4-phenyloxybenzyl)-2-methyl-amino]-2-phenyl-acetamide; and

(R)-2-[[4-(3-fluorophenyloxy)benzyl]-2-cyclopropyl-amino]-2-phenyl-acetamide.

EXAMPLE 3

With the usual methods of pharmaceutical technique, preparation can bemade of capsules having the following composition:

2-[4-(3-fluorobenzyloxy)benzylamino]-2- 50 mg phenyl-acetamide,methanesulfonate Talc  2 mg Corn starch  2 mg Microcristalline cellulose 6 mg Magnesium stearate  1 mg

What is claimed is:
 1. A compound which is a substituted2-benzylamino-2-phenyl acetamide of formula (I)

wherein: n is zero, 1, 2 or 3; X is —O—, —S—, —CH₂— or —NH—; each of R,R₁ , R₂ and R₃, independently, is hydrogen, C₁-C₆ alkyl, halogen,hydroxy, C₁-C₆ alkoxy or trifluoromethyl; each of R₄ and R₅,independently, is hydrogen, C₁-C₆ alkyl or C₃-C₇ cycloalkyl; or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1, wherein n is 1 or 2; X is —O—; each of R, R₁, R₂ and R₃,independently, is hydrogen, or halogen; R₄ and R₅ are hydrogen.
 3. Acompound according to claim 1, which is selected from:2-[4-benzyloxybenzylamino]-2-phenyl-acetamide;2-[4-(3-fluorobenzyloxy)benzylamino]-2-phenyl-acetamide;2-[4-(3-chlorobenzyloxy)benzylamino]-2-phenyl-acetamide;2-[4-(3-bromobenzyloxy)benzylamino]-2-phenyl-acetamide;2-[4-(2-fluorobenzyloxy)benzylamino]-2-phenyl-acetamide;2-[4-(3-fluorobenzyloxy)benzylamino]-2-(2-fluorophenyl)-acetamide;2-[4-(3-fluorobenzyloxy)benzylamino]-2-(3-fluorophenyl)-acetamide; and2-[4-(3-chlorobenzyloxy)benzylamino]-2-(3-fluorophenyl)-acetamide, ifthe case either as a single isomer or as a mixture thereof, or apharmaceutically acceptable salt thereof.
 4. A pharmaceuticalcomposition comprising a pharmaceutically acceptable excipient and, asan active agent, a compound as defined in claim
 1. 5. A compound asdefined in claim 1, for use in a method of treatment of the human oranimal body by therapy.
 6. A compound as claimed in claim 5 for use inregulating a physiological condition related to sodium channel blockade.7. A compound as claimed in claim 5, for use in treating chronic orneuropathic pain.
 8. A method of treating a mammal, including a human,in need of a sodium channel-blocking agent, said method comprisingadministering thereto an effective amount of a compound of formula (I)or a pharmaceutically acceptable salt thereof.
 9. A method according toclaim 8 wherein the mammal is suffering from chronic or neuropathicpain.